U.S. patent application number 09/886612 was filed with the patent office on 2003-04-24 for orthomolecular sulpho-adenosylmethionine derivatives with antioxidant properties.
Invention is credited to Wilburn, Michael D..
Application Number | 20030078231 09/886612 |
Document ID | / |
Family ID | 25389374 |
Filed Date | 2003-04-24 |
United States Patent
Application |
20030078231 |
Kind Code |
A1 |
Wilburn, Michael D. |
April 24, 2003 |
Orthomolecular sulpho-adenosylmethionine derivatives with
antioxidant properties
Abstract
Orthomolecular Sulpho-Adenosylmethionine derivative compounds,
compositions, and their uses for effecting a biological activity in
an animal, such as neurochemical activity; liver biology activity;
heart and artery function; cartilage, bone and joint health;
stomach and/or intestinal lining resistance to ulceration; immune
function; cell membrane integrity; and pain and inflammation. The
compounds of the present invention are further useful for
preventing or treating diseases or conditions; treating viral
infections, infectious diseases, leukemia, and obesity; and
reducing the risk of Sudden Infant Death Syndrome in an animal. The
compounds of the present invention are of formula I: 1 A is 0 or N;
and X is a reaction product as defined herein.
Inventors: |
Wilburn, Michael D.; (Cedar
Hill, TX) |
Correspondence
Address: |
NATH & ASSOCIATES
1030 15th STREET
6TH FLOOR
WASHINGTON
DC
20005
US
|
Family ID: |
25389374 |
Appl. No.: |
09/886612 |
Filed: |
June 22, 2001 |
Current U.S.
Class: |
514/45 ;
536/27.3 |
Current CPC
Class: |
C07H 19/16 20130101 |
Class at
Publication: |
514/45 ;
536/27.3 |
International
Class: |
A61K 031/7076; C07H
019/16 |
Claims
We claim:
1. A compound of formula I: 11or a pharmaceutically acceptable
salt, ester, or solvate, thereof, wherein: R.sub.1 is hydrogen,
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or alkynyl, or
--C(O)R.sub.2 where R.sub.2 is C.sub.1-C.sub.10 alkyl or
C.sub.2-C.sub.10 alkenyl or alkynyl; Q is 12wherein A is O or N;
and X is G, M, Y, or Z; wherein G is a reaction product derived
from a reactant compound selected from the group consisting of
.alpha.-butyric acid, 3-methoxy-4-hydroxymandelic acid,
3-carboxy-3-aminopropyl analogues, e.g., wye base and diphthamide,
5-phosphoribose-1-pyrophosphoric acid, 6-gingerol,
acetyl-L-carnitine, acetylcholine, ajoene,
aminocyclopropane-carboxylic acid (ACC), anserine, anthocyanin,
apigenin, arachidonic acid, astaxanthin, betaine, biopterin,
calcium pectate, carbamyl phosphate, carnitine, carnosine,
catechin, chlorogenic acid, choline, creatine, creatinine,
cryptoxanthin, cumic acid, cumidine, curcumin, cyanidin chloride,
d-limonene, daidzein, diacylglycerol, dopamine, ellagic acid,
epicatechin, epicatechin gallate, epigallocatechin,
epigallocatechin gallate, epinephrine, farnesyl, fibronectins,
fisetin, (flavan-3-ol).sub.n, wherein n is 1-12, flavoxanthine,
fructose 1,6-bisphosphate, gallic acid, genistein, geranyl,
ginkgolide A, ginkgolide B, ginkgolide C, glucose, glutathione,
GTP, hesperidin, hesperitin, histamine, HMG Co-A, homoserine
lactone, indole-3-carbinol, kynurenine, L-dopa, L-histidine,
linatine, lipoic acid, lupeol, lutein, luteolin, lycophyll,
lycoxanthine, lysine, lysolecithin, mandelic acid, melanins,
melatonin, metanephrine, methylated estrogen, methylated lipids,
N-methylglycine, N-methyl histamine, N-malonyl ACC, neopterin,
nervonic acid, N,N-dimethylglycine, N,N-dimethyltryptamine,
norepinephrine, normetanephrine, ornithine, p-coumaric acid,
pectin, phosphocreatine, phytic acid, phytochlorin, phytol,
picolinic acid, proanthocyanin, pyruvate, quercetin, queuine,
queuosine, quinolinic acid, rutin, S-allymercaptocysteine,
sarcosine, serotonin, sesamin, silybin, sulphorane, taurine,
taxicatin, taxicin I, taxicin II, taxifolin, taxine A, taxodione,
tetrahydrobiopterin and derivatives, trimethylysine, tryptamine,
tumeric, vaccenic acid, vanillic acid, xanthophyll, xanthoxylin, or
zeaxanthin; wherein M is a straight or branched C.sub.1-C.sub.11
alkyl, or C.sub.2-C.sub.11 straight or branched alkenyl or alkynyl,
wherein said alkyl, alkenyl, and alkynyl is substituted with 1 to 8
substituents selected from the group consisting of hydroxy,
carboxy, amino, and --SH, wherein said hydroxy, carboxy, amino, or
--SH substituent is optionally substituted; M is further optionally
substituted with 1 to 8 substituents selected from the group
consisting of halo, nitro, double-bonded oxygen, methoxy, and
C.sub.2-C.sub.8 straight or branched alkoxy; and wherein one or
more carbon atom(s) of said alkyl, alkenyl, or alkynyl is
optionally replaced with nitrogen, oxygen, or sulfur; wherein Y is
a straight or branched C.sub.12-C.sub.30 alkyl, alkenyl, or alkynyl
optionally substituted with 1 to 12 substituents selected from the
group consisting of hydroxy, carboxy, amino, halo, nitro, --SH, and
J, wherein J is phenyl or a 5-7 membered O-heterocyclic ring, and J
is optionally substituted with 1 to 5 substituents selected from
the group consisting of hydroxy, carboxy, amino, halo, nitro, --SH,
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or alkynyl,
methoxy, C.sub.2-C.sub.8 straight or branched alkoxy, and
--OC(O)R.sub.2 where R.sub.2 is C.sub.1-C.sub.10 alkyl or
C.sub.2-C.sub.10 alkenyl or alkynyl, wherein said hydroxy, carboxy,
amino, halo, nitro, --SH, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10
alkenyl or alkynyl, methoxy, C.sub.2-C.sub.8 straight or branched
alkoxy, and --OC(O)R.sub.2 substituents are optionally substituted;
and wherein one or more carbon atom(s) of said alkyl, alkenyl,
alkynyl, or alkoxy, is optionally replaced with nitrogen, oxygen,
or sulfur; and wherein Z is phenyl substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-C.sub.8
straight or branched alkyl, hydroxy, carboxy, amino, and --SH; and
Z is further optionally substituted with 1 to 3 substituents
selected from the group consisting of halo, nitro, C.sub.1-C.sub.8
straight or branched alkyl, C.sub.2-C.sub.8 straight or branched
alkenyl or alkynyl, methoxy, and C.sub.2-C.sub.8 straight or
branched alkoxy, wherein said hydroxy, carboxy, amino, --SH, halo,
nitro, C.sub.1-C.sub.8 straight or branched alkyl, C.sub.2-C.sub.8
straight or branched alkenyl or alkynyl, methoxy, and
C.sub.2-C.sub.8 straight or branched alkoxy substituents are
optionally substituted; and wherein one or more carbon atom(s) of
said alkyl, alkenyl, alkynyl, or alkoxy, is optionally replaced
with nitrogen, oxygen, or sulfur.
2. The compound of claim 1, wherein R.sub.1 is hydrogen, methyl, or
--C(O)CH.sub.3.
3. The compound of claim 1, wherein A is oxygen.
4. The compound of claim 3, wherein X is Y and J is phenyl.
5. The compound of claim 4, wherein Q is
(2,6-di(tert-butyl))4-methylpheno- l.
6. The compound of claim 1, wherein X is M.
7. The compound of claim 1, wherein X is Y.
8. The compound of claim 1, wherein X is Z.
9. A pharmaceutical composition comprising: (i) a compound of
formula (I): 13or a pharmaceutically acceptable salt, ester, or
solvate, thereof, wherein: R.sub.1 is hydrogen, C.sub.1-C.sub.10
alkyl, C.sub.2-C.sub.10 alkenyl or alkynyl, or --C(O)R.sub.2 where
R.sub.2 is C.sub.1-C.sub.10 alkyl or C.sub.2-C.sub.10 alkenyl or
alkynyl; Q is 14wherein A is O or N; and X is G, M, Y, or Z;
wherein G is a reaction product derived from a reactant compound
selected from the group consisting of .alpha.-butyric acid,
3-methoxy-4-hydroxymandelic acid, 3-carboxy-3-aminopropyl
analogues, e.g., wye base and diphthamide, 5-phosphoribose-1-
pyrophosphoric acid, 6-gingerol, acetyl-L-carnitine, acetylcholine,
ajoene, aminocyclopropane-carboxylic acid (ACC), anserine,
anthocyanin, apigenin, arachidonic acid, astaxanthin, betaine,
biopterin, calcium pectate, carbamyl phosphate, carnitine,
carnosine, catechin, chlorogenic acid, choline, creatine,
creatinine, cryptoxanthin, cumic acid, cumidine, curcumin, cyanidin
chloride, d-limonene, daidzein, diacylglycerol, dopamine, ellagic
acid, epicatechin, epicatechin gallate, epigallocatechin,
epigallocatechin gallate, epinephrine, farnesyl, fibronectins,
fisetin, (flavan-3-ol).sub.n, wherein n is 1-12, flavoxanthine,
fructose 1,6-bisphosphate, gallic acid, genistein, geranyl,
ginkgolide A, ginkgolide B, ginkgolide C, glucose, glutathione,
GTP, hesperidin, hesperitin, histamine, HMG Co-A, homoserine
lactone, indole-3-carbinol, kynurenine, L-dopa, L-histidine,
linatine, lipoic acid, lupeol, lutein, luteolin, lycophyll,
lycoxanthine, lysine, lysolecithin, mandelic acid, melanins,
melatonin, metanephrine, methylated estrogen, methylated lipids,
N-methylglycine, N-methyl histamine, N-malonyl ACC, neopterin,
nervonic acid, N,N-dimethylglycine, N,N-dimethyltryptamine,
norepinephrine, normetanephrine, ornithine, p-coumaric acid,
pectin, phosphocreatine, phytic acid, phytochlorin, phytol,
picolinic acid, proanthocyanin, pyruvate, quercetin, queuine,
queuosine, quinolinic acid, rutin, S-allymercaptocysteine,
sarcosine, serotonin, sesamin, silybin, sulphorane, taurine,
taxicatin, taxicin I, taxicin II, taxifolin, taxine A, taxodione,
tetrahydrobiopterin and derivatives, trimethylysine, tryptamine,
tumeric, vaccenic acid, vanillic acid, xanthophyll, xanthoxylin, or
zeaxanthin; wherein M is a straight or branched C.sub.1-C.sub.11
alkyl, or C.sub.2-C.sub.11 straight or branched alkenyl or alkynyl,
wherein said alkyl, alkenyl, and alkynyl is substituted with 1 to 8
substituents selected from the group consisting of hydroxy,
carboxy, amino, and --SH, wherein said hydroxy, carboxy, amino, or
--SH substituent is optionally substituted; M is further optionally
substituted with 1 to 8 substituents selected from the group
consisting of halo, nitro, double-bonded oxygen, methoxy, and
C.sub.2-C.sub.8 straight or branched alkoxy; and wherein one or
more carbon atom(s) of said alkyl, alkenyl, or alkynyl is
optionally replaced with nitrogen, oxygen, or sulfur; wherein Y is
a straight or branched C.sub.12-C.sub.30 alkyl, alkenyl, or alkynyl
optionally substituted with 1 to 12 substituents selected from the
group consisting of hydroxy, carboxy, amino, halo, nitro, --SH, and
J, wherein J is phenyl or a 5-7 membered O-heterocyclic ring, and J
is optionally substituted with 1 to 5 substituents selected from
the group consisting of hydroxy, carboxy, amino, halo, nitro, --SH,
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or alkynyl,
methoxy, C.sub.2-C.sub.8 straight or branched alkoxy, and
--OC(O)R.sub.2 where R.sub.2 is C.sub.1-C.sub.10 alkyl or
C.sub.2-C.sub.10 alkenyl or alkynyl, wherein said hydroxy, carboxy,
amino, halo, nitro, --SH, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.11
alkenyl or alkynyl, methoxy, C.sub.2-C.sub.8 straight or branched
alkoxy, and --OC(O)R.sub.2 substituents are optionally substituted;
and wherein one or more carbon atom(s) of said alkyl, alkenyl,
alkynyl, or alkoxy, is optionally replaced with nitrogen, oxygen,
or sulfur; and wherein Z is phenyl substituted with 1 to 5
substituents selected from the group consisting of C.sub.1-C.sub.8
straight or branched alkyl, hydroxy, carboxy, amino, and --SH; and
Z is further optionally substituted with 1 to 3 substituents
selected from the group consisting of halo, nitro, C.sub.1-C.sub.8
straight or branched alkyl, C.sub.2-C.sub.8 straight or branched
alkenyl or alkynyl, methoxy, and C.sub.2-C.sub.8 straight or
branched alkoxy, wherein said hydroxy, carboxy, amino, --SH, halo,
nitro, C.sub.1-C.sub.8 straight or branched alkyl, C.sub.2-C.sub.8
straight or branched alkenyl or alkynyl, methoxy, and
C.sub.2-C.sub.8 straight or branched alkoxy substituents are
optionally substituted; and wherein one or more carbon atom(s) of
said alkyl, alkenyl, alkynyl, or alkoxy, is optionally replaced
with nitrogen, oxygen, or sulfur; and (ii) a pharmaceutically
acceptable carrier.
10. The pharmaceutical composition of claim 9, wherein said
compound methylates a target molecule in vitro.
11. The pharmaceutical composition of claim 10, wherein said target
molecule is a protein, nucleic acid, lipid, glycoprotein, or
glycolipid.
12. The pharmaceutical composition of claim 9, wherein the carrier
is a sterile solution, suspension or emulsion, in a single or
divided dose.
13. The pharmaceutical composition of claim 9, wherein the carrier
is a capsule or tablet containing a single or divided dose of said
compound.
14. The pharmaceutical composition of claim 9, wherein the carrier
comprises a biodegradable polymer.
15. The pharmaceutical composition of claim 14, wherein the
biodegradable polymer releases the compound of formula I over a
prolonged period of time.
16. The pharmaceutical composition of claim 9, wherein the carrier
is a solid implant.
17. A method for effecting a biological activity in an animal,
which comprises administering to said animal an effective amount of
a compound of formula I of claim 1, wherein the biological activity
selected from the group consisting of neurochemical activity; liver
biology activity; heart and artery function; cartilage, bone and
joint health; stomach and/or intestinal lining resistance to
ulceration; immune function; cell membrane integrity; and pain and
inflammation; treating or preventing diseases or conditions;
treating viral infections, infectious diseases, and leukemia;
reducing the risk of Sudden Infant Death Syndrome; and control of
obesity.
18. The method of claim 17, wherein the disease or condition is
selected from the group consisting of tissue damage resulting from
physical trauma, tissue damage resulting from cell damage or cell
death due to necrosis or apoptosis, neuronal mediated tissue damage
or diseases, neural tissue damage resulting from ischemia and
reperfusion injury, neurological disorders and neurodegenerative
diseases, vascular stroke, cardiovascular disorders, age-related
macular degeneration, AIDS and other immune diseases, arthritis,
atherosclerosis, cachexia, cancer, degenerative diseases of
skeletal muscle involving replicative senescence, diabetes, head
trauma, immune senescence, inflammatory bowel disorders, muscular
dystrophy, osteoarthritis, osteoporosis, chronic pain, acute pain,
neuropathic pain, nervous insult, peripheral nerve injury, renal
failure, retinal ischemia, septic shock, skin aging, altered
circadian rhythmicicty, obesity, sickle cell anemia, cystic
fibrosis, diseases or disorders relating to lifespan or
proliferative capacity of cells, and diseases or disease conditions
induced or exacerbated by cellular senescence.
19. The method of claim 17, wherein said effect on neurochemical
activity is selected from the group consisting of treating anxiety;
treating depression; treating depression secondary to a chronic
disease; treating dementia; treating schizophrenia; treating
Alzheimer's disease; treating Parkinson's disease; treating
demyelinating disorders; treating peripheral neuropathies; treating
uremic neuropathy; treating Grand Mal seizures; treating Tay-Sachs
disease; treating epilepsy; enhancing mood and behavior; and
maintaining or effecting neuronal membrane ratios of phosphatidyl
choline and cholesterol.
20. The method of claim 17, wherein said effect on liver biology
activity is selected from the group consisting of treating
cirrhosis, chronic liver disease, alcoholic liver damage, toxic
chemical exposure, NSAID-liver damage, estrogen induced liver
problems, bile disorders, and environmental chemical
hypersensitivity.
21. The method of claim 17, wherein said effect on heart and artery
function is treating or reducing heart and/or artery disease risk
due to elevated blood levels of homocysteine.
22. The method of claim 17, wherein said effect on cartilage, bone
and joint health is selected from the group consisting of treating
osteoarthritis, rheumatoid arthritis, fibromyalgia, joint injuries,
joint inflammation, joint degeneration, and osteoporosis.
23. The method of claim 17, wherein said effect on immune function
is selected from the group consisting of treating organ transplant
rejection, graft rejection, lupus, uveitis, Behcet's disease,
Graves disease, Guillain-Barre syndrome, psoriasis, acute
dermatomyositis, atopic skin disease, scleroderma, eczema, aplastic
anemia, primary cirrhosis, autoimmune hepatitis, ulcerative
colitis, Crohn's disease, amyotrophic lateral sclerosis, myasthenia
gravis, multiple sclerosis, nephrotic syndrome, glomerulonephritis,
rheumatoid arthritis, and diabetes mellitus.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of Invention
[0002] The present invention relates to novel compounds and
pharmaceutical preparations including the same which are useful in
effecting a biological activity in an animal, such as neurochemical
activity; liver biology activity; heart and artery function;
cartilage, bone and joint health; stomach and/or intestinal lining
resistance to ulceration; immune function; cell membrane integrity;
and pain and inflammation; in preventing or treating diseases or
conditions; in treating viral infections, infectious diseases,
leukemia, and obesity; and in reducing the risk of Sudden Infant
Death Syndrome.
[0003] 2. Background
[0004] Linus Pauling coined the term "Orthomolecular Medicine" and
defined it as: "The preservation of good health and the prevention
and treatment of disease by varying the concentrations in the human
body of the molecules or substances that are normally present, many
of them required for life, such as the vitamins, essential amino
acids, essential fats, and minerals." Literally, the term is
derived from the Greek "ortho", for correct or right, and
"molecule", or "right molecule". When these "right molecules" are
out of balance, disorders and disease can result. The
Orthomolecular Concomitant Theory of Convergence suggests that the
duality of stress and uncontrolled free radical proliferation are
major disruptive forces in the delicate balance of life, resulting
in disorders, diseases, and premature death. In particular, the
free radical theory of aging and disease suggests that excess free
radicals can be generated by stress, simple aging, exposure to
toxic pollutants in air, water, and foods, as well as cigarette
smoke, alcohol, and ionizing radiation. Free radicals may produce
oxidative damage to DNA and other cell components which accumulates
with age and is suggested to be a major contributor to aging and
degenerative diseases. Antioxidants may be used for reducing,
eliminating, preventing, and reversing oxidative damage to tissues
in an animal. Treatment of disorders and disease by orthomolecular
methods is aimed at bringing such natural substances into healthful
balance.
[0005] In a relatively recent phenomenon, traditional primary
health care practitioners have begun to embrace orthomolecular
nutrition as an enhancement to their practices. There are several
forces promoting this trend, including consumer demand and the
increasing eligibility of alternative health care for medical
insurance coverage.
[0006] The National Institutes of Health (NIH) has established the
National Center for Complementary and Alternative Medicine (NCCAM)
to assist in prioritizing applications for research grants in
complementary and alternative medicine (CAM). The NCCAM
classification system is divided into seven major categories and
includes examples of practices or preparations in each category.
The biologically-based therapies category includes natural and
biologically-based practices, interventions, and products. One
subcategory is orthomolecular medicine, which refers to products
used as nutritional and food supplements for preventive or
therapeutic purposes. The NCCAM classification system lists
Ascorbic Acid, Carotenes, Tocopherols, Folic Acid, Niacin,
Niacinamide, Pantothenic Acid, Pyridoxine, Riboflavin, Thiamine,
Vitamin A, Vitamin D, Vitamin K, Biotin, Choline,
S-adenosylmethionine, Calcium, Magnesium, Selenium, Potassium,
Taurine, Lysine, Tyrosine, Gamma-oryzanol, Iodine, Iron, Manganese,
Molybdenum, Boron, Silicon, Vanadium, Co-enzyme Q.sub.10,
Carnitine, Probiotics, Glutamine, Phenylalanine, Glucosamine
Sulfate, Chondroitin Sulfate, Lipoic Acid, Amino Acids,
Phosphatidylserine, Melatonin, DHEA, Inositol, Glandular Products,
Fatty Acids, and Medium Chain Triglycerides as examples of
orthomolecular substances. Other examples of orthomolecular
substances include Omega-3 fatty acids, lycopene, soy
isoflavonoids, tocotrienols, chromium, zinc, and copper.
[0007] Sulpho-Adenosylmethionine, also known as S-adenosyl
methionine or SAM, was first discovered in 1952 and has been
commercially available in Europe since the 1970's. SAM appears to
be an important compound that occurs in many living cells and takes
part in several biological processes in the human body. U.S. Pat.
No. 6,020,139 (Feb. 1, 2000) claims "a method to identify a
therapeutic composition or protocol which ameliorates a disease or
undesired condition in a subject, which method relies upon
recognition of the existence of, and the interconnections between,
eight SAM pathways" described therein and slates that "a new
paradigm of disease centers around the metabolic pathways of
S-adenosyl-L-methionine (SAM), the intermediates of these pathways
and other metabolic pathways influenced by the SAM pathways."
[0008] SAM is the key to at least three major biochemical pathways,
including transmethylation, transsulfuration, and aminopropylation,
which regulate or impact virtually every biochemical reaction in
humans and animals (see FIG. 1). Neurochemistry; liver biology;
heart and artery function; cartilage, bone, and joint health;
stomach and intestinal lining resistance to ulceration; immune
health; cell membrane integrity; pain and inflammation; resistance
to viral infections and infectious diseases; response to leukemia;
resistance to Sudden Infant Death Syndrome; and control of obesity
are just some of the biological systems influenced by the
efficiency or inefficiency of SAM metabolism. Pathways involving
SAM also require a variety of vitamins and cofactors.
[0009] Transmethylation is essential to many biochemical processes:
methyltransferase reactions shift a methyl group from a methyl
donor molecule, such as SAM, to a methyl acceptor molecule (see
FIG. 1), including biogenic amines (e.g. noradrenaline, serotonin),
fatty acids and phospholipids, proteins, nucleic acids,
polysaccharides, and porphyrins. SAM appears to be the most
important methyl group donor in mammalian tissue. Methyl groups
donated by SAM make possible the production of carnitine;
acetyl-L-carnitine; creatine phosphate; adrenaline; phosphatidyl
choline; and methyladenine and methylcytosine, among many other
critical methylated biomolecules. Transmethylation byproduct
homocysteine may be recycled via the methionine cycle to produce
SAM (see FIGS. 1 and 2).
[0010] The transsulfuration pathway (see FIGS. 1 and 2) begins with
transmethylation byproduct S-Adenosylhomocysteine (SAH). SAH is
processed to yield homocysteine, which may be converted to taurine,
sulfates, or cysteine. Cysteine may in turn produce a family of key
sulphur compounds, including glutathione (GSH), GSH peroxidase, and
GSH-S-transferase. SAM may also provide the sulphur for glucosamine
sulphate and chondroitin sulphate. GSH, GSH compounds, and taurine
play critical roles in liver detoxification of foreign and
metabolic toxins. Failure to complete the transsulfuration pathway,
or to recycle homocysteine via the methionine cycle, may result in
the accumulation of homocysteine, which is toxic to heart and
arterial tissues, and is a significant risk factor for
cardio-pulmonary disorders.
[0011] Aminopropylation reactions utilizing SAM convert putrescine
to spermidine and spermine (see FIG. 1), which play key roles in
cell growth and differentiation, gene expression, and protein
phosphorylation, calcium homeostasis, and neuronal regeneration.
Methylthioadenosine is one byproduct of polyamine production and
possesses potentially important analgesic and anti-inflammatory
characteristics.
[0012] The novel compounds of the present invention have
surprisingly been found to effect a variety of biological systems
and processes, including neurochemical activity; liver biology
activity; heart and artery function; cartilage, bone and joint
health; stomach and/or intestinal lining resistance to ulceration;
immune function; cell membrane integrity; pain and inflammation;
resistance to viral infections and infectious diseases; response to
leukemia; reducing the risk of Sudden Infant Death Syndrome; and
control of obesity. Without being bound to a particular theory or
mechanism of action, it appears that covalently linking SAM to a
compound with antioxidant properties as disclosed herein may
enhance the activity of SAM and/or the antioxidant compound in the
relevant biochemical pathway.
[0013] Although others have recently recognized the significance of
orthomolecular methods, Applicant is one of the pioneers in the
field. In U.S. Pat. Nos. 5,108,754 (Apr. 28, 1992) and 5,177,208
(Jan. 5, 1993), Applicant obtained patent protection for novel
compounds, compositions, and an orthomolecular method for treating
sickle cell disease.
[0014] Other U.S. Patents for orthomolecular methods, as such,
include the following: U.S. Pat. No. 4,500,515, for a method for
treating alcohol and drug addicts; U.S. Pat. No.4,876,278, for zinc
glycerolate complex and additions for pharmaceutical applications;
U.S. Pat. Nos. 4,918,102 and 5,013,752, for prevention and
treatment of alcoholism by the use of dietary chromium; U.S. Pat.
Nos. 5,070,101 and 5,177,081, for a method and pharmaceutical
composition for the treatment of schizophrenia; U.S. Pat. No.
5,230,996, for the use of ascorbate and tranexamic acid solution
for organ and blood vessel treatment prior to transplantation; U.S.
Pat. No. 5,278,189, for the prevention and treatment of occlusive
cardiovascular disease with ascorbate and substances that inhibit
the binding of lipoprotein (A) ; U.S. Pat. No. 5,869,525, for
ascorbic acid drugs for intracerebral administration; U.S. Pat.
Nos. 5,874,471 and 6,028,107, for the orthomolecular medical use of
L-citrulline for vasoprotection, relaxative smooth muscle tone and
cell protection; U.S. Pat. No. 5,897,891, for flavorful zinc
compositions for oral use incorporating copper; and U.S. Pat. No.
6,039,978, for a dietary food enhancement agent.
[0015] Methods of producing stable SAM salts, both biologically and
chemically (see U.S. Pat. Nos. 4,558,122, 4,621,056, 4,990,606,
5,102,791, 5,166,328, 5,114,931, and 5,128,249), are known in the
art. Applicant has described a process for the synthesis of the SAM
derivative .alpha.-(S-adenosylmethionine)-O-tocopherol in U.S. Pat.
Nos. 5,108,754 and 5,177,208. All of the publications, patents, and
other references cited in this application are incorporated by
reference as though set forth in full.
[0016] Use of SAM alone is known in the art. Unexpectedly, it has
been discovered that the novel compounds of the present invention
may enhance the activity of SAM and/or a covalently-linked compound
with antioxidant properties in the relevant biochemical pathway
effecting neurochemical activity; liver biology activity; heart and
artery function; cartilage, bone and joint health; stomach and/or
intestinal lining resistance to ulceration; reducing the risk of
Sudden Infant Death Syndrome; immune function; cell membrane
integrity; and pain and inflammation in an animal. Further, such
covalently linked conjugates are effective in preventing or
treating diseases or conditions; and treating viral infections,
infectious diseases, leukemia, and obesity in an animal.
[0017] All of the publications, patents, and other references cited
herein are incorporated by reference as though set forth in
full.
SUMMARY OF THE INVENTION
[0018] The present invention relates to a novel
Sulpho-Adenosylmethionine derivative compound of formula I: 2
[0019] or a pharmaceutically acceptable salt, ester, or solvate,
thereof, wherein:
[0020] R.sub.1 is hydrogen, C.sub.1-C.sub.10 alkyl,
C.sub.2-C.sub.10 alkenyl or alkynyl, or --C(O)R.sub.2 where R.sub.2
is C.sub.1-C.sub.10 alkyl or C.sub.2-C.sub.10 alkenyl or
alkynyl;
[0021] Q is 3
[0022] wherein
[0023] A is O or N; and
[0024] X is G, M, Y, or Z;
[0025] wherein G is a reaction product derived from a reactant
compound selected from the group consisting of .alpha.-butyric
acid, 3-methoxy-4-hydroxymandelic acid, 3-carboxy-3-aminopropyl
analogues, e.g., wye base and diphthamide,
5-phosphoribose-1-pyrophosphoric acid, 6-gingerol,
acetyl-L-carnitine, acetylcholine, ajoene,
aminocyclopropane-carboxylic acid (ACC), anserine, anthocyanin,
apigenin, arachidonic acid, astaxanthin, betaine, biopterin,
calcium pectate, carbamyl phosphate, carnitine, carnosine,
catechin, chlorogenic acid, choline, creatine, creatinine,
cryptoxanthin, cumic acid, cumidine, curcumin, cyanidin chloride,
d-limonene, daidzein, diacylglycerol, dopamine, ellagic acid,
epicatechin, epicatechin gallate, epigallocatechin,
epigallocatechin gallate, epinephrine, farnesyl, fibronectins,
fisetin, (flavan-3-ol).sub.n, wherein n is 1-12, flavoxanthine,
fructose 1,6-bisphosphate, gallic acid, genistein, geranyl,
ginkgolide A, ginkgolide B, ginkgolide C, glucose, glutathione,
GTP, hesperidin, hesperitin, histamine, HMG Co-A, homoserine
lactone, indole-3-carbinol, kynurenine, L-dopa, L-histidine,
linatine, lipoic acid, lupeol, lutein, luteolin, lycophyll,
lycoxanthine, lysine, lysolecithin, mandelic acid, melanins,
melatonin, metanephrine, methylated estrogen, methylated lipids,
N-methylglycine, N-methyl histamine, N-malonyl ACC, neopterin,
nervonic acid, N,N-dimethylglycine, N,N-dimethyltryptamine,
norepinephrine, normetanephrine, ornithine, p-coumaric acid,
pectin, phosphocreatine, phytic acid, phytochlorin, phytol,
picolinic acid, proanthocyanin, pyruvate, quercetin, queuine,
queuosine, quinolinic acid, rutin, S-allymercaptocysteine,
sarcosine, serotonin, sesamin, silybin, sulphorane, taurine,
taxicatin, taxicin I, taxicin II, taxifolin, taxine A, taxodione,
tetrahydrobiopterin and derivatives, trimethylysine, tryptamine,
tumeric, vaccenic acid, vanillic acid, xanthophyll, xanthoxylin, or
zeaxanthin;
[0026] wherein M is a straight or branched C.sub.1-C.sub.11 alkyl,
or C.sub.2-C-.sub.11 straight or branched alkenyl or alkynyl,
wherein said alkyl, alkenyl, and alkynyl is substituted with 1 to 8
substituents selected from the group consisting of hydroxy,
carboxy, amino, and --SH, wherein said hydroxy, carboxy, amino, or
--SH substituent is optionally substituted; M is further optionally
substituted with 1 to 8 substituents selected from the group
consisting of halo, nitro, double-bonded oxygen, methoxy, and
C.sub.2-C.sub.8 straight or branched alkoxy; and wherein one or
more carbon atom(s) of said alkyl, alkenyl, or alkynyl is
optionally replaced with nitrogen, oxygen, or sulfur;
[0027] wherein Y is a straight or branched C.sub.12-C.sub.30 alkyl,
alkenyl, or alkynyl optionally substituted with 1 to 12
substituents selected from the group consisting of hydroxy,
carboxy, amino, halo, nitro, --SH, and J, wherein J is phenyl or a
5-7 membered O-heterocyclic ring, and J is optionally substituted
with 1 to 5 substituents selected from the group consisting of
hydroxy, carboxy, amino, halo, nitro, --SH, C.sub.1-C.sub.10 alkyl
C.sub.2-C.sub.10 alkenyl or alkynyl, methoxy, C.sub.2-C.sub.8
straight or branched alkoxy, and --OC(O)R.sub.2 where R.sub.2 is
C.sub.1-C.sub.10 alkyl or C.sub.2-C.sub.10 alkenyl or alkynyl,
wherein said hydroxy, carboxy, amino, halo, nitro, --SH,
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or alkynyl,
methoxy, C.sub.2-C.sub.8 straight or branched alkoxy, and
--OC(O)R.sub.2 substituents are optionally substituted; and wherein
one or more carbon atom(s) of said alkyl, alkenyl, alkynyl, or
alkoxy, is optionally replaced with nitrogen, oxygen, or sulfur;
and
[0028] wherein Z is phenyl substituted with 1 to 5 substituents
selected from the group consisting of C.sub.1-C.sub.8 straight or
branched alkyl, hydroxy, carboxy, amino, and --SH; and Z is further
optionally substituted with 1 to 3 substituents selected from the
group consisting of halo, nitro, C.sub.1-C.sub.8 straight or
branched alkyl, C.sub.2-C.sub.8 straight or branched alkenyl or
alkynyl, methoxy, and C.sub.2-C.sub.8 straight or branched alkoxy,
wherein said hydroxy, carboxy, amino, --SH, halo, nitro,
C.sub.1-C.sub.8 straight or branched alkyl, C.sub.2-C.sub.8
straight or branched alkenyl or alkynyl, methoxy, and
C.sub.2-C.sub.8 straight or branched alkoxy substituents are
optionally substituted; and wherein one or more carbon atom(s) of
said alkyl, alkenyl, alkynyl, or alkoxy, is optionally replaced
with nitrogen, oxygen, or sulfur.
[0029] The present invention further relates to a method for
preventing or treating diseases or conditions; effecting
neurochemical activity; effecting liver biology activity; effecting
heart and artery function; effecting cartilage, bone and joint
health; effecting stomach and/or intestinal lining resistance to
ulceration; effecting immune function; effecting cell membrane
integrity; and effecting pain and inflammation in an animal, which
comprises administering to said animal an effective amount of a
Sulpho-Adenosylmethionine derivative compound of formula T.
[0030] Finally, the present invention relates to a pharmaceutical
composition comprising:
[0031] (i) an effective amount of a Sulpho-Adenosylmethionine
derivative compound of formula I; and
[0032] (ii) a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] FIG. 1 is a drawing which depicts three major metabolic
pathways in which Sulpho-Adenosylmethionine (SAM) is a key factor:
transmethylation, transsulfuration, and aminopropylation.
[0034] FIG. 2 is a drawing which depicts homocysteine metabolism
via the methionine cycle and the transsulfuration pathway.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
[0035] "Effecting" refers to the process of producing an effect on
biological activity, function, health, or condition of an organism
in which such biological activity, function, health, or condition
is maintained, enhanced, diminished, or treated in a manner which
is consistent with the general health and well-being of the
organism.
[0036] "Enhancing" the biological activity, function, health, or
condition of an organism refers to the process of augmenting,
fortifying, strengthening, or improving.
[0037] "Isomers" refer to different compounds that have the same
molecular formula. "Stereoisomers" are isomers that differ only in
the way the atoms are arranged in space. "Enantiomers" are a pair
of stereoisomers that are non-superimposable mirror images of each
other. "Diastereoisomers" are stereolsomers which are not mirror
images of each other. "Racemic mixture" means a mixture containing
equal parts of individual enantiomers. "Non-racemic mixture" is a
mixture containing unequal parts of individual enantiomers or
stereoisomers.
[0038] "Pharmaceutically acceptable salt, ester, or solvate" refers
to a salt, ester, or solvate of a subject compound which possesses
the desired pharmacological activity and which is neither
biologically nor otherwise undesirable. A salt, ester, or solvate
can be formed with inorganic acids such as acetate, adipate,
alginate, aspartate, benzoate, benzenesulfonate, bisulfate,
butyrate, citrate, camphorate, camphorsulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, glucoheptanoate, gluconate,
glycerophosphate, hemisulfate, heptanoate, hexanoate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
lactate, maleate, methanesulfonate, naphthylate,
2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate,
tosylate and undecanoate. Examples of base salts, esters, or
solvates include ammonium salts; alkali metal salts, such as sodium
and potassium salts; alkaline earth metal salts, such as calcium
and magnesium salts; salts with organic bases, such as
dicyclohexylamine salts; N-methyl-D-glucamine; and salts with amino
acids, such as arginine, lysine, and so forth. Also, the basic
nitrogen-containing groups can be quarternized with such agents as
lower alkyl halides, such as methyl, ethyl, propyl, and butyl
chlorides, bromides, and iodides; dialkyl sulfates, such as
dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain
halides, such as decyl, lauryl, myristyl, and stearyl chlorides,
bromides, and iodides; aralkyl halides, such as benzyl and
phenethyl bromides; and others. Water or oil-soluble or dispersible
products are thereby obtained.
[0039] It is to be understood that, in its most common form, a
"reactant compound" within the scope of the present invention may
or may not have the reactive moiety(ies) necessary to produce a
compound of the present invention. It is intended that such
compound(s) will be derivatized to add one or more reactive
moiety(ies) by means known to one of ordinary skill in the art. By
way of example and not limitation, appropriate derivatives may be
produced by hydration, halogenation, carboxylation, amination,
nitration, and sulfonation.
[0040] "Reaction product" refers to that part of a reactant
compound remaining after the chemical reaction producing a
covalently-linked compound of the present invention. Such chemical
reactions include substitution, elimination, addition, oxidation,
and reduction reactions, and involve reactive moieties such as
multiple bonds; oxygen and hydroxyl; nitrogen, nitro, amide, and
amine; sulfur, sulfhydryl, and sulpho; and other common groups
known to one of ordinary skill in the art.
[0041] "Sulpho-Adenosylmethionine", or SAM, refers to a compound of
the following formula: 4
[0042] "Treating" refers to:
[0043] (i) preventing a disease and/or condition from occurring in
a subject which may be predisposed to the disease and/or condition
but has not yet been diagnosed as having it;
[0044] (ii) inhibiting the disease and/or condition, i.e.,
arresting its development; or
[0045] (iii) relieving the disease and/or condition, i.e., causing
regression of the disease and/or condition.
ORTHOMOLECULAR SULPHO-ADENOSYLMETHIONINE DERIVATIVES
[0046] The present invention relates to novel
Sulpho-Adenosylmethionine derivative compounds of Formula I.
Formula I
[0047] The Sulpho-Adenosylmethionine derivative may be a compound
of formula I: 5
[0048] or a pharmaceutically acceptable salt, ester, or solvate,
thereof, wherein:
[0049] R.sub.1 Is hydrogen, C.sub.1-C.sub.10 alkyl,
C.sub.2-C.sub.10 alkenyl or alkynyl, or --C(O)R.sub.2 where R.sub.2
is C.sub.1-C.sub.10 alkyl or C.sub.2-C.sub.10 alkenyl or
alkynyl;
[0050] Q is 6
[0051] A is O or N; and
[0052] X is G, M, Y, or Z;
[0053] wherein G is a reaction product derived from a reactant
compound selected from the group consisting of .alpha.-butyric
acid, 3-methoxy-4-hydroxymandelic acid, 3-carboxy-3-aminopropyl
analogues, e.g., wye base and diphthamide,
5-phosphoribose-1-pyrophosphoric acid, 6-gingerol,
acetyl-L-carnitine, acetylcholine, ajoene,
aminocyclopropane-carboxylic acid (ACC), anserine, anthocyanin,
apigenin, arachidonic acid, astaxanthin, betaine, biopterin,
calcium pectate, carbamyl phosphate, carnitine, carnosine,
catechin, chlorogenic acid, choline, creatine, creatinine,
cryptoxanthin, cumic acid, cumidine, curcumin, cyanidin chloride,
d-limonene, daidzein, diacylglycerol, dopamine, ellagic acid,
epicatechin, epicatechin gallate, epigallocatechin,
epigallocatechin gallate, epinephrine, farnesyl, fibronectins,
fisetin, (flavan-3-ol).sub.n, wherein n is 1-12, flavoxanthine,
fructose 1,6-bisphosphate, gallic acid, genistein, geranyl,
ginkgolide A, ginkgolide B, ginkgolide C, glucose, glutathione,
GTP, hesperidin, hesperitin, histamine, HMG Co-A, homoserine
lactone, indole-3-carbinol, kynurenine, L-dopa, L-histidine,
linatine, lipoic acid, lupeol, lutein, luteolin, lycophyll,
lycoxanthine, lysine, lysolecithin, mandelic acid, melanins,
melatonin, metanephrine, methylated estrogen, methylated lipids,
N-methylglycine, N-methyl histamine, N-malonyl ACC, neopterin,
nervonic acid, N,N-dimethylglycine, N,N-dimethyltryptamine,
norepinephrine, normetanephrine, ornithine, p-coumaric acid,
pectin, phosphocreatine, phytic acid, phytochlorin, phytol,
picolinic acid, proanthocyanin, pyruvate, quercetin, queuine,
queuosine, quinolinic acid, rutin, S-allymercaptocysteine,
sarcosine, serotonin, sesamin, silybin, sulphorane, taurine,
taxicatin, taxicin I, taxicin II, taxifolin, taxine A, taxodione,
tetrahydrobiopterin and derivatives, trimethylysine, tryptamine,
tumeric, vaccenic acid, vanillic acid, xanthophyll, xanthoxylin, or
zeaxanthin;
[0054] wherein M is a straight or branched C.sub.1-C.sub.11 alkyl,
or C.sub.2-C.sub.11 straight or branched alkenyl or alkynyl,
wherein said alkyl, alkenyl, and alkynyl is substituted with 1 to 8
substituents selected from the group consisting of hydroxy,
carboxy, amino, and --SH, wherein said hydroxy, carboxy, amino, or
--SH substituent is optionally substituted; M is further optionally
substituted with 1 to 8 substituents selected from the group
consisting of halo, nitro, double-bonded oxygen, methoxy, and
C.sub.2-C.sub.8 straight or branched alkoxy; and wherein one or
more carbon atom(s) of said alkyl, alkenyl, or alkynyl is
optionally replaced with nitrogen, oxygen, or sulfur;
[0055] wherein Y is a straight or branched C.sub.12-C.sub.30 alkyl,
alkenyl, or alkynyl optionally substituted with 1 to 12
substituents selected from the group consisting of hydroxy,
carboxy, amino, halo, nitro, --SH, and J, wherein J is phenyl or a
5-7 membered O-heterocyclic ring, and J is optionally substituted
with 1 to 5 substituents selected from the group consisting of
hydroxy, carboxy, amino, halo, nitro, --SH, C.sub.1-C.sub.10 alkyl,
C.sub.2-C.sub.10 alkenyl or alkynyl, methoxy, C.sub.2-C.sub.8
straight or branched alkoxy, and --OC(O)R.sub.2 where R.sub.2 is
C.sub.1-C.sub.10 alkyl or C.sub.2-C.sub.10 alkenyl or alkynyl,
wherein said hydroxy, carboxy, amino, halo, nitro, --SH,
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or alkynyl,
methoxy, C.sub.2-C.sub.8 straight or branched alkoxy, and
--OC(O)R.sub.2 substituents are optionally substituted; and wherein
one or more carbon atom(s) of said alkyl, alkenyl, alkynyl, or
alkoxy, is optionally replaced with nitrogen, oxygen, or sulfur;
and
[0056] wherein Z is phenyl substituted with 1 to 5 substituents
selected from the group consisting of C.sub.1-C.sub.8 straight or
branched alkyl, hydroxy, carboxy, amino, and --SH; and Z is further
optionally substituted with 1 to 3 substituents selected from the
group consisting of halo, nitro, C.sub.1-C.sub.8 straight or
branched alkyl, C.sub.2-C.sub.8 straight or branched alkenyl or
alkynyl, methoxy, and C.sub.2-C.sub.8 straight or branched alkoxy,
wherein said hydroxy, carboxy, amino, --SH, halo, nitro,
C.sub.1-C.sub.8 straight or branched alkyl, C.sub.2-C.sub.8
straight or branched alkenyl or alkynyl, methoxy, and
C.sub.2-C.sub.8 straight or branched alkoxy substituents are
optionally substituted; and wherein one or more carbon atom(s) of
said alkyl, alkenyl, alkynyl, or alkoxy, is optionally replaced
with nitrogen, oxygen, or sulfur.
[0057] In a preferred embodiment, Q is
(2,6-di(tert-butyl))4-methylphenol.
METHODS OF THE PRESENT INVENTION
[0058] The present invention relates to a method for effecting
neurochemical activity; effecting liver biology activity; effecting
heart and artery function; effecting cartilage, bone and joint
health; effecting stomach and/or intestinal lining resistance to
ulceration; effecting immune function; effecting cell membrane
integrity; and effecting pain and inflammation; preventing or
treating diseases or conditions; treating viral infections;
treating infectious diseases; treating leukemia; reducing the risk
of Sudden Infant Death Syndrome; and treating obesity in an animal,
which comprises administering to said animal an effective amount of
a Sulpho-Adenosylmethionine derivative compound of formula I or
formula II.
[0059] In a preferred embodiment, the disease(s) or condition(s) to
be prevented or treated is/are selected from the group consisting
of tissue damage resulting from physical trauma, tissue damage
resulting from cell damage or cell death due to necrosis or
apoptosis, neuronal mediated tissue damage or diseases, neural
tissue damage resulting from ischemia and reperfusion injury,
neurological disorders and neurodegenerative diseases, vascular
stroke, cardiovascular disorders, age-related macular degeneration,
AIDS and other immune diseases, arthritis, atherosclerosis,
cachexia, cancer, degenerative diseases of skeletal muscle
involving replicative senescence, diabetes, head trauma, immune
senescence, inflammatory bowel disorders, muscular dystrophy,
osteoarthritis, osteoporosis, chronic pain, acute pain, neuropathic
pain, nervous insult, peripheral nerve injury, renal failure,
retinal ischemia, septic shock, skin aging, altered circadian
rhythmicicty, obesity, sickle cell anemia, cystic fibrosis,
diseases or disorders relating to lifespan or proliferative
capacity of cells, and diseases or disease conditions induced or
exacerbated by cellular senescence.
[0060] In another preferred embodiment, the effect on neurochemical
activity is selected from the group consisting of treating anxiety;
treating depression; treating depression secondary to chronic
diseases such as arthritis, fibromyalgia, liver disease, sickle
cell disease, and alcoholism; treating dementia; treating
schizophrenia; treating Alzheimer's disease; treating Parkinson's
disease; treating demyelinating disorders; treating peripheral
neuropathies; treating uremic neuropathy; treating Grand Mal
seizures; treating Tay-Sachs disease; treating epilepsy; enhancing
mood and behavior; and maintaining or effecting neuronal membrane
ratios of phosphatidyl choline and cholesterol.
[0061] In another preferred embodiment, the effect on liver biology
activity is selected from the group consisting of treating
cirrhosis, chronic liver disease, alcoholic liver damage, toxic
chemical exposure, non-steroidal anti-inflammatory drug-related
liver damage, estrogen induced liver problems, bile disorders, and
environmental chemical hypersensitivity.
[0062] In another preferred embodiment, the effect on heart and
artery function is treating or reducing heart and/or artery disease
risk due to elevated blood levels of homocysteine.
[0063] In a further preferred embodiment, the effect on cartilage,
bone and joint health is selected from the group consisting of
treating osteoarthritis, rheumatoid arthritis, fibromyalgia, joint
injuries, joint inflammation, joint degeneration, and
osteoporosis.
[0064] In another preferred embodiment, the effect on immune
function is selected from the group consisting of treating organ
transplant and graft rejection of non-self tissue, and treating
autoimmune diseases involving the rejection of self tissue, such as
lupus, uveitis, Behcet's disease, Graves disease, Guillain-Barre
syndrome, psoriasis, acute dermatomyositis, atopic skin disease,
scleroderma, eczema, aplastic anemia, primary cirrhosis, autoimmune
hepatitis, ulcerative colitis, Crohn's disease, amyotrophic lateral
sclerosis, myasthenia gravis, multiple sclerosis, nephrotic
syndrome, glomerulonephritis, rheumatoid arthritis, and diabetes
mellitus.
PHARMACEUTICAL COMPOSITIONS OF THE PRESENT INVENTION
[0065] The present invention also relates to a pharmaceutical
composition comprising:
[0066] (i) an effective amount of a Sulpho-Adenosylmethionine
derivative compound of formula I ; and
[0067] (ii) a pharmaceutically acceptable carrier.
[0068] The novel pharmaceutical compositions of the invention
include a therapeutically effective amount of the active agent
indicated above. This effective amount will generally comprise from
about 0.1 mg to about 100 mg of the active agent per kilogram of
patient body weight per day. This effective amount can vary
depending upon the physical status of the patient and other factors
well known in the art. Moreover, it will be understood that this
dosage of active agent can be administered in a single or multiple
dosage units to provide the desired therapeutic effect. If desired,
other therapeutic agents can be employed in conjunction with those
provided by the present invention.
[0069] The compounds of the invention are preferably delivered to
the patient by means of a pharmaceutically acceptable carrier. Such
carriers are well known in the art and generally will be in either
solid or liquid form. Solid form pharmaceutical preparations which
may be prepared according to the present invention include powders,
tablets, dispersible granules, capsules, cachets and suppositories.
In general, solid form preparations will comprise from about 5% to
about 90% by weight of the active agent.
[0070] A solid carrier can be one or more-substances which may also
act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders or tablet disintegrating agents; it can
also be encapsulating material. In powders, the carrier is a finely
divided solid which is in admixture with the viscous active
compound. In tablets, the active compound is mixed with a carrier
having the necessary binding properties in suitable proportions and
compacted to the shape and size desired. Suitable solid carriers
include magnesium carbonate, magnesium stearate, talc, sugar,
lactose, pectin, dextrin, starch, gelatin, tragacanth,
methylcellulose, sodium carboxymethylcellulose, a low melting wax,
cocoa butter, and the like. The term "preparation" is intended to
include the formulation of the active compound with encapsulating
materials as a carrier which may provide a capsule in which the
active component (with or without other carriers) is surrounded by
carrier, which is thus in association with it. Similarly, cachets
are included. Tablets, powders, cachets, and capsules can be used
as solid dosage forms suitable for oral administration. If desired
for reasons of convenience or patient acceptance, pharmaceutical
tablets prepared according to the invention may be provided in
chewable form, using techniques well known in the art.
[0071] For preparing suppositories, a low melting wax such as a
mixture of fatty acid glycerides or cocoa butter is first melted,
and the active ingredient is dispersed homogeneously therein as by
stirring. The molten homogeneous mixture is then poured into
convenient sized molds, allowed to cool and thereby to
solidify.
[0072] Liquid form preparations include solutions, suspensions, and
emulsions. As an example may be mentioned water or water/propylene
glycol solutions for parenteral injection. Liquid preparations can
also be formulated in solution in aqueous polyethylene glycol
solution. Aqueous solutions suitable for oral use can be prepared
by dissolving the active component in water and adding suitable
colorants, flavors, stabilizers and thickening agents as desired.
Aqueous suspensions suitable for oral use can be made my dispersing
the finely divided active component in water with a viscous
material, i.e., natural or synthetic gums, resins, methylcellulose,
sodium carboxymethylcellulose, and other well known suspending
agents. Liquid pharmaceutical preparations may comprise up to 100%
by weight of the subject active agent.
[0073] Also contemplated as suitable carriers are solid form
preparations which are intended to be converted, shortly before
use, to liquid form preparations for either oral or parenteral
administration. Such liquid forms include solutions, suspensions,
and emulsions. These particular solid form preparations are most
conveniently provided in unit dose form and as such are used to
provide a single liquid dosage unit. Alternately, sufficient solid
may be provided so that after conversion to liquid form, multiple
individual liquid doses may be obtained by measuring predetermined
volumes of the liquid form preparation as with a syringe, teaspoon,
or other volumetric container. When multiple liquid doses are so
prepared, it is preferred to maintain the unused portion of said
liquid doses at low temperature (i.e., under refrigeration) in
order to retard possible decomposition. The solid form preparations
intended to be converted to liquid form may contain, in addition to
the active material, flavorants, colorants, stabilizers, buffers,
artificial and natural sweeteners, dispersants, thickeners,
solubilizing agents, and the like. The liquid utilized for
preparing useful liquid form preparations may be water, isotonic
water, ethanol, glycerine, propylene glycol, and the like as well
as mixtures thereof. Naturally, the liquid utilized will be chosen
with regard to the route of administration. For example, liquid
preparations containing large amounts of ethanol are not suitable
for parenteral use.
[0074] The pharmaceutical preparation may also be in a unit dosage
form. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of preparation, for example, packeted tablets,
capsules, and powders in vials or ampoules. The unit dosage form
can also be a capsule, cachet, or tablet itself or it can be the
appropriate number of any of these in packaged form.
[0075] The pharmaceutical preparations of the invention may include
one or more preservatives well known in the art, such as benzoic
acid, sorbic acid, methylparaben, propylparaben and
ethylenediaminetetraacetic acid (EDTA). Preservatives are generally
present in amounts up to about 1% and preferably from about 0.05 to
about 0.5% by weight of the pharmaceutical composition.
[0076] Useful buffers for purposes of the invention include citric
acid-sodium citrate, phosphoric acid-sodium phosphate, and acetic
acid-sodium acetate in amounts up to about 1% and preferably from
about 0.05 to about 0.5% by weight of the pharmaceutical
composition. Useful suspending agents or thickeners include
cellulosics like methylcellulose, carageenans like alginic acid and
its derivatives, xanthan gums, gelatin, acacia, and
microcrystalline cellulose in amounts up to about 20% and
preferably from about 1% to about 15% by weight of the
pharmaceutical composition.
[0077] Sweeteners which may be employed include those sweeteners,
both natural and artificial, well known in the art. Sweetening
agents such as monosaccharides, disaccharides and polysaccharides
such as xylose, ribose, glucose, mannose, galactose, fructose,
dextrose, sucrose, maltose, partially hydrolyzed starch or corn
syrup solids and sugar alcohols such as sorbitol, xylitol, mannitol
and mixtures thereof may be utilized in amounts from about 10% to
about 60% and preferably from about 20% to about 50% by weight of
the pharmaceutical composition. Water soluble artificial sweeteners
such as saccharin and saccharin salts such as sodium or calcium,
cyclamate salts, acesulfame-K, aspartame and the like and mixtures
thereof may be utilized in amounts from about 0.001% to about 5% by
weight of the composition.
[0078] Flavorants which may be employed in the pharmaceutical
products of the invention include both natural and artificial
flavors, and mints such as peppermint, menthol, vanilla, artificial
vanilla, chocolate, artificial chocolate, cinnamon, various fruit
flavors, both individually and mixed, in amounts from about 0.5% to
about 5% by weight of the pharmaceutical composition.
[0079] Colorants useful in the present invention include pigments
which may be incorporated in amounts of up to about 6% by weight of
the composition. A preferred pigment, titanium dioxide, may be
incorporated in amounts up to about 1%. Also, the colorants may
include other dyes suitable for food, drug and cosmetic
applications, known as F.D.&C. dyes and the like. Such dyes are
generally present in amounts up to about 0.25% and preferably from
about 0.05% to about 0.2% by weight of the pharmaceutical
composition. A full recitation of all F.D.&C. and D.&C.
dyes and their corresponding chemical structures may be found in
the Kirk-Othmer Encyclopedia of Chemical Technology, in Volume 5,
at pages 857-884, which text is accordingly incorporated herein by
reference.
[0080] Useful solubilizers include alcohol, propylene glycol,
polyethylene glycol and the like and may be used to solubilize the
flavors. Solubilizing agents are generally present in amounts up to
about 10%; preferably from about 2% to about 5% by weight of the
pharmaceutical composition.
[0081] Lubricating agents which may be used when desired in the
instant compositions include silicone oils or fluids such as
substituted and unsubstituted polysiloxanes, e.g., dimethyl
polysiloxane, also known as dimethicone. Other well known
lubricating agents may be employed.
[0082] It is not expected that compounds of the present invention
will display significant adverse interactions with other synthetic
or naturally occurring substances. Thus, a
Sulpho-Adenosylmethionine derivative compound of the present
invention may be administered in combination with other compounds
and compositions useful for effecting neurochemical activity; liver
biology activity; heart and artery function; cartilage, bone and
joint health; stomach and/or intestinal lining resistance to
ulceration; immune function; cell membrane integrity; and pain and
inflammation; treating viral infections, infectious diseases,
leukemia, and obesity; and reducing the risk of Sudden Infant Death
Syndrome. In particular the compounds of the present invention may
be administered in combination with other compounds of the present
invention; other orthomolecular substances; vitamin(s) and/or
cofactor(s) selected from the group consisting of Vitamin A,
.beta.-Carotene, Vitamin B.sub.1 (Thiamine), Vitamin B.sub.2
(Riboflavin), Vitamin B.sub.6 (Pyrodoxine), Biotin, Inositol, Folic
Acid, Vitamin B.sub.12 (Cyanocobalamine), Nicotinic Acid, Vitamin C
(esterified or non-esterified Ascorbic Acid), Vitamin D
(Ergocalciferol), Pantothenic Acid, Phosphatidyl Choline,
Tetrahydrofolate, Tetrahydrobiopterin, .beta.-tocopherol,
.gamma.-tocopherol, .delta.-tocopherol, .alpha.-tocotrienol,
.beta.-tocotrienol, .gamma.-tocotrienol, .delta.-tocotrienol,
Para-aminobenzoic Acid (PABA), and Inosinate; other known
over-the-counter and/or prescription drugs; and other compounds and
compositions useful for effecting neurochemical activity; liver
biology activity; heart and artery function; cartilage, bone and
joint health; stomach and/or intestinal lining resistance to
ulceration; immune function; cell membrane integrity; and pain and
inflammation; treating viral infections, infectious diseases,
leukemia, and obesity; and reducing the risk of Sudden Infant Death
Syndrome.
[0083] The optimal pharmaceutical formulations will be determined
by one skilled in the art depending upon considerations such as the
route of administration and desired dosage. See, for example,
"Remington's Pharmaceutical Sciences", 18th ed. (1990, Mack
Publishing Co., Easton, Pa. 18042), pp. 1435-1712, the disclosure
of which is hereby incorporated by reference. Such formulations may
influence the physical state, stability, rate of in vivo release,
and rate of in vivo clearance of the present therapeutic agents of
the invention.
Synthesis of Sulpho-Adenosylmethionine Derivatives
[0084] The compounds of the present invention may be readily
prepared by standard techniques of organic chemistry, utilizing the
general synthetic pathways depicted below.
[0085] In the preparation of the compounds of the invention, one
skilled in the art will understand that one may need to protect or
block various reactive functionalities on the starting compounds or
intermediates while a desired reaction is carried out on other
portions of the molecule. After the desired reactions are complete,
or at any desired time, normally such protecting groups will be
removed by, for example, hydrolytic or hydrogenolytic means. Such
protection and deprotection steps are conventional in organic
chemistry. One skilled in the art is referred to "Protective Groups
in Organic Chemistry," McOmie, ed., Plenum Press, New York, N.Y.;
and "Protective Groups in Organic Synthesis," Greene, ed., John
Wiley & Sons, New York, N.Y. (1981) for the teaching of
protective groups which may be useful in the preparation of
compounds of the present invention.
[0086] The product and intermediates may be isolated or purified
using one or more standard purification techniques, including, for
example, one or more of simple solvent evaporation,
recrystallization, distillation, sublimation, filtration,
chromatography, including thin-layer chromatography, HPLC (e.g.
reverse phase HPLC), column chromatography, flash chromatography,
radial chromatography, trituration, and the like.
SCHEME I
[0087] As depicted by Scheme I, a radical of .alpha.-butyric acid,
3-methoxy-4-hydroxymandelic acid, 3-carboxy-3-aminopropyl
analogues, e.g., wye base and diphthamide,
5-phosphoribose-1-pyrophosphoric acid, 6-gingerol,
acetyl-L-carnitine, acetylcholine, ajoene,
aminocyclopropane-carboxylic acid (ACC), anserine, anthocyanin,
apigenin, arachidonic acid, astaxanthin, betaine, biopterin,
calcium pectate, carbamyl phosphate, carnitine, carnosine,
catechin, chlorogenic acid, choline, creatine, creatinine,
cryptoxanthin, cumic acid, cumidine, curcumin, cyanidin chloride,
d-limonene, daidzein, diacylglycerol, dopamine, ellagic acid,
epicatechin, epicatechin gallate, epigallocatechin,
epigallocatechin gallate, epinephrine, farnesyl, fibronectins,
fisetin, (flavan-3-ol).sub.n, wherein n is 1-12, flavoxanthine,
fructose 1,6-bisphosphate, gallic acid, genistein, geranyl,
ginkgolide A, ginkgolide B, ginkgolide C, glucose, glutathione,
GTP, hesperidin, hesperitin, histamine, HMG Co-A, homoserine
lactone, indole-3-carbinol, kynurenine, L-dopa, L-histidine,
linatine, lipoic acid, lupeol, lutein, luteolin, lycophyll,
lycoxanthine, lysine, lysolecithin, mandelic acid, melanins,
melatonin, metanephrine, methylated estrogen, methylated lipids,
N-methylglycine, N-methyl histamine, N-malonyl ACC, neopterin,
nervonic acid, N,N-dimethylglycine, N,N-dimethyltryptamine,
norepinephrine, normetanephrine, ornithine, p-coumaric acid,
pectin, phosphocreatine, phytic acid, phytochlorin, phytol,
picolinic acid, proanthocyanin, pyruvate, quercetin, queuine,
queuosine, quinolinic acid, rutin, S-allymercaptocysteine,
sarcosine, serotonin, sesamin, silybin, sulphorane, taurine,
taxicatin, taxicin I, taxicin II, taxifolin, taxine A, taxodione,
tetrahydrobiopterin and derivatives, trimethylysine, tryptamine,
tumeric, vaccenic acid, vanillic acid, xanthophyll, xanthoxylin, or
zeaxanthin bearing a free hydroxyl (from --OH or --COOH) or amine
functional group may be covalently attached to S-adenosylmethionine
to produce a compound of formula I: 7
[0088] wherein X is 0 or NH.
SCHEME II
[0089] As depicted by Scheme II, a radical of .alpha.-butyric acid,
3-methoxy-4-hydroxymandelic acid, 3-carboxy-3-aminopropyl
analogues, e.g., wye base and diphthamide,
5-phosphoribose-l-pyrophosphoric acid, 6-gingerol,
acetyl-L-carnitine, acetylcholine, ajoene,
aminocyclopropane-carboxylic acid (ACC), anserine, anthocyanin,
apigenin, arachidonic acid, astaxanthin, betaine, biopterin,
calcium pectate, carbamyl phosphate, carnitine, carnosine,
catechin, chlorogenic acid, choline, creatine, creatinine,
cryptoxanthin, cumic acid, cumidine, curcumin, cyanidin chloride,
d-limonene, daidzein, diacylglycerol, dopamine, ellagic acid,
epicatechin, epicatechin gallate, epigallocatechin,
epigallocatechin gallate, epinephrine, farnesyl, fibronectins,
fisetin, (flavan-3-ol).sub.n, wherein n is 1-12, flavoxanthine,
fructose 1,6-bisphosphate, gallic acid, genistein, geranyl,
ginkgolide A, ginkgolide B, ginkgolide C, glucose, glutathione,
GTP, hesperidin, hesperitin, histamine, HMG Co-A, homoserine
lactone, indole-3-carbinol, kynurenine, L-dopa, L-histidine,
linatine, lipoic acid, lupeol, lutein, luteolin, lycophyll,
lycoxanthine, lysine, lysolecithin, mandelic acid, melanins,
melatonin, metanephrine, methylated estrogen, methylated lipids,
N-methylglycine, N-methyl histamine, N-malonyl ACC, neopterin,
nervonic acid, N,N-dimethylglycine, N,N-dimethyltryptamine,
norepinephrine, normetanephrine, ornithine, p-coumaric acid,
pectin, phosphocreatine, phytic acid, phytochlorin, phytol,
picolinic acid, proanthocyanin, pyruvate, quercetin, queuine,
queuosine, quinolinic acid, rutin, S-allymercaptocysteine,
sarcosine, serotonin, sesamin, silybin, sulphorane, taurine,
taxicatin, taxicin I, taxicin II, taxifolin, taxine A, taxodione,
tetrahydrobiopterin and derivatives, trimethylysine, tryptamine,
tumeric, vaccenic acid, vanillic acid, xanthophyll, xanthoxylin, or
zeaxanthin, bearing a free hydroxyl (from --OH or --COOH) or amine
functional group may be covalently attached to S-adenosylmethionine
to produce a compound of formula II: 8
[0090] wherein X is O or NH.
SCHEME III
[0091] A representative example of the synthesis of a compound of
formula I, covalently linking a radical of curcumin with
S-adenosylmethionine, is depicted in Scheme 9
[0092] Where the radical-forming non-SAM constituent possesses more
than one --OH, NH.sub.2, or --COOH group which can be used to
generate more than one radical to be linked to SAM, then each and
every possible radical is within the scope of the present
invention. The product and intermediates may be synthesized and
isolated or purified employing one or more standard
protecting/deprotecting steps and purification techniques as
discussed above.
SCHEME IV
[0093] As depicted by Scheme IV, stable salts of
S-adenosylmethionine may be synthesized as described below: 10
[0094] As described by the methods herein incorporated by
reference, salts of SAM may be formed independently at each of
R.sub.1, R.sub.2 or R.sub.3. For example, one or more of R.sub.1,
R.sub.2 or R.sub.3 can remain as hydrogen while the other R groups
may be formed as salts. The synthetic methods for producing stable
salts (see U.S. Pat. Nos. 4,558,122 and 5,166,328) are known in the
art. U.S. Pat. Nos. 4,558,122 and 5,166,328 are incorporated herein
by reference as though set forth in full.
[0095] Stable salts of SAM as described by Scheme IV can optionally
be used in place of S-adenosylmethionine in Schemes I, II, and III
to synthesize stable salts of compounds of formula I.
Route(s) of Administration
[0096] The route(s) of administration of the compounds and
compositions of the present invention are well known to those
skilled in the art (see, for example, "Remington's Pharmaceutical
Sciences", 18th Edition, Chapter 86, pp. 1581-1592, Mack Publishing
Company, 1990). The compounds and compositions may be administered
orally, parenterally, by inhalation spray, topically, rectally,
nasally, buccally, vaginally, or via an implanted reservoir in
dosage formulations containing conventional non-toxic
pharmaceutically-acceptable carriers, adjuvants, and vehicles. The
term parenteral as used herein includes subcutaneous, intravenous,
intramuscular, intraperitoneally, intrathecally,
intraventricularly, intrasternal, and intracranial injection or
infusion techniques.
[0097] To be effective therapeutically as central nervous system
targets, the compounds and compositions should readily penetrate
the blood-brain barrier when peripherally administered. Compounds
which cannot penetrate the blood-brain barrier can be effectively
administered by an intraventricular route.
[0098] The compounds and compositions may be administered in the
form of sterile injectable preparations, for example, as sterile
injectable aqueous or oleaginous suspensions. These suspensions,
may be formulated according to techniques known in the art using
suitable dispersing or wetting agents and suspending agents. The
sterile injectable preparations may also be sterile injectable
solutions or suspensions in non-toxic parenterally-acceptable
diluents or solvents, for example, as solutions in 1,3-butanediol.
Among the acceptable vehicles and solvents that may be employed are
water, Ringer's solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as
solvents or suspending mediums. For this purpose, any bland fixed
oil such as a synthetic mono- or di-glyceride may be employed.
Fatty acids such as oleic acid and its glyceride derivatives,
including olive oil and castor oil, especially in their
polyoxyethylated versions, are useful in the preparation of
injectables. These oil solutions or suspensions may also contain
long-chain alcohol diluents or dispersants.
[0099] Additionally, in a preferred embodiment, the compounds and
compositions may be administered orally in the form of capsules,
tablets, aqueous suspensions, or solutions. Tablets may contain
carriers such as lactose and corn starch, and/or lubricating agents
such as magnesium stearate. Capsules may contain diluents including
lactose and dried corn starch. Aqueous suspensions may contain
emulsifying and suspending agents combined with the active
ingredient. The oral dosage forms may further contain sweetening,
flavoring, coloring agents, or combinations thereof. Delivery in an
enterically coated tablet, caplet, or capsule, to further enhance
stability and provide release in the intestinal tract to improve
absorption, is the best mode of administration currently
contemplated.
[0100] The compounds may also be administered rectally in the form
of suppositories. These compositions can be prepared by mixing the
drug with a suitable non-irritating excipient which is solid at
room temperature, but liquid at rectal temperature and, therefore,
will melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax, and polyethylene glycols.
[0101] Furthermore, the compounds may be administered topically,
especially when the conditions addressed for treatment involve
areas or organs readily accessible by topical application,
including the lower intestinal tract. Suitable topical formulations
can be readily prepared for such areas or organs. For example,
topical application to the lower intestinal tract can be effected
in a rectal suppository formulations (see above) or in suitable
enema formulations.
[0102] It is envisioned that the continuous administration or
sustained delivery of the compounds and compositions of the present
invention may be advantageous for a given condition. While
continuous administration may be accomplished via a mechanical
means, such as with an infusion pump, it is contemplated that other
modes of continuous or near continuous administration may be
practiced. For example, such administration may be by subcutaneous
or muscular injections as well as oral pills.
[0103] Techniques for formulating a variety of other sustained- or
controlled-delivery means, such as liposome carriers, bio-erodible
particles or beads and depot injections, are also known to those
skilled in the art.
Dosage
[0104] Dosage levels on the order of about 0.001 mg to about 100 mg
per kilogram body weight of the active ingredient compounds or
compositions are useful in the treatment of the above conditions,
with preferred levels ranging from 2.0 mg to 16 mg per day per
kilogram body weight. The compounds and compositions of the present
invention may usually be given in two or three doses daily.
Starting with a low dose (200-300 mg) twice daily and slowly
working up to higher doses if needed is a preferred strategy. The
amount of active ingredient that may be combined with the carrier
materials to produce a single dosage form will vary depending upon
the host treated and the particular mode of administration.
[0105] It is understood, however, that a specific dose level for
any particular patient will depend upon a variety of factors,
including the activity of the specific compound employed; the age,
body weight, general health, sex and diet of the patient; the time
of administration; the rate of excretion; drug combination; the
severity of the particular disorder being treated; and the form of
administration. One of ordinary skill in the art would appreciate
the variability of such factors and would be able to establish
specific dose levels using no more than routine
experimentation.
EXAMPLES
[0106] The following examples are illustrative of the present
invention and are not intended to be limitations thereon. Unless
otherwise indicated, all percentages are based upon 100% by weight
of the final composition.
Example 1
Preparation of .alpha.-(S-adenosylmethionine)-O-tocopherol
[0107] N-Acetyl-S-benzyl-L-homocysteine (0.5 g) was dissolved in
1,4-dioxane (25 ml). Dicyclohexyl carbodiimide (0.5 g) was added to
the solution with stirring followed by the addition of
.alpha.-tocopherol (1 g). The resulting reaction mixture was
stirred at 30.degree.-32.degree. C. for eighteen (18) hours during
which time a white precipitate separated. The mixture was then
filtered and the filtrate evaporated to dryness in vacuo to give an
expected oily residue.
[0108] The oily residue was added to dry ammonia (ca. 100 ml) which
had been previously condensed in a 500 ml three-necked flask
equipped with a stirrer and sodium hydroxide tube to maintain
anhydrous conditions. While stirring, sodium was added to the
reaction mixture in small pieces until the resulting blue color
persisted for 5-10 minutes.
[0109] 5'-O-p-Tolyl-sulfonyladenosine (0.5 g) was then added to the
solution and stirring continued for ten (10) minutes. The ammonia
was evaporated for three hours and the final traces thereof removed
under diminished pressure, yielding a waxy solid residue. The
residue was extracted with methylene chloride (2.times.25 ml) and
the combined residue evaporated to dryness to give a waxy
solid.
[0110] The waxy solid was dissolved in dimethyl sulfoxide (10 ml)
containing acetic acid (3 ml) and the solution stirred with excess
methyl iodide (1 ml) for 30 hours at 30.degree.-32.degree. C. The
solvent was allowed to evaporate and the resulting residue was
extracted with methylene chloride (25 ml) and dried with sodium
sulfate. Evaporation of the solvent gave a clear oil which turned
green when exposed to air.
[0111] The expected compound,
.alpha.-(S-adenosylmethionine)-O-tocopherol, was recovered and
stored for future use.
Example 2
[0112] A patient is suffering from depression. An
S-adenosylmethionine derivative as identified above, or a
pharmaceutical composition comprising the same, may be administered
to the patient. Reduction or elimination of depression and mood
enhancement are expected to occur following treatment.
Example 3
[0113] A patient is suffering from a liver disease or disorder
involving hepatic glutathione levels. An S-adenosylmethionine
derivative as identified above, or a pharmaceutical composition
comprising the same, may be administered to the patient.
Enhancement of liver detoxification function is expected to occur
following treatment.
Example 4
[0114] A patient is suffering from impaired heart and/or artery
function resulting from elevated blood levels of homocysteine. An
S-adenosylmethionine derivative as identified above, or a
pharmaceutical composition comprising the same, may be administered
to the patient. Enhancement of heart and/or artery function, and/or
reduction in heart and/or artery disease risk is expected to occur
following treatment.
Example 5
[0115] A patient is suffering from degenerative joint disease. An
S-adenosylmethionine derivative as identified above, or a
pharmaceutical composition comprising the same, may be administered
to the patient. Stimulation of chondrocytes to increase production
of new cartilage and enhancement of joint health, mobility, and
comfort are expected to occur following treatment.
Example 6
[0116] A patient is suffering from a disease or disease condition
induced or exacerbated by cellular senescence. An
S-adenosylmethionine derivative as identified above, or a
pharmaceutical composition comprising the same, may be administered
to the patient. Reduction or elimination of cellular senescence is
expected to occur following treatment.
[0117] The invention being thus described, it will be obvious that
the same may be varied in many ways. Such variations are not to be
regarded as a departure from the spirit and scope of the invention
and all such modifications are intended to be included within the
scope of the following claims.
* * * * *